Base Editing (ABE8e) for MPL c.304C>T (p.Arg102Cys) in Thrombocytopenia, congenital amegakaryocytic, 1

Base Editing (ABE8e) via RNP electroporation (ex vivo) delivery is a rationale-driven therapeutic strategy for Thrombocytopenia, congenital amegakaryocytic, 1 targeting the MPL c.304C>T (p.Arg102Cys) variant (Pathogenic, missense variant). The editing system (ABE8e-nSpCas9 (adenine base editor)) converts the pathogenic A back to G on the target strand, restoring the wild-type codon. Target tissue: Blood/HSC. Therapeutic goal: Correct biallelic loss-of-function MPL variants in hematopoietic stem and progenitor cells to restore thrombopoietin signaling, normalize megakaryopoiesis, and prevent progression to bone marrow failu. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Medium, immunogenicity Low.

1. Molecular basis: MPL NM_005373.3(MPL):c.304C>T (p.Arg102Cys) is classified as Pathogenic (ClinVar variation ID 644406). Molecular consequence: missense variant. Protein change: R102C. 2. Epidemiology: Ultra-rare inherited bone marrow failure syndrome with fewer than 100 reported cases worldwide and estimated prevalence <1/1,000,000; most cases present in the neonatal period with severe thrombocytopenia and progress to pancytopenia and marrow failure in early childhood (WEB-01, WEB-03, WEB-09, PAP 3. Standard of care: Supportive care with platelet transfusions and aggressive management of bleeding, followed by early allogeneic hematopoietic stem cell transplantation (HSCT) which is the only established curative option for MPL-associated CAMT1. Thrombopoietin receptor agonists (eltrombopag, romiplostim) show littl 4. Pipeline: No registered interventional trials or approved gene therapies specifically targeting MPL in CAMT1 were identified in ClinicalTrials.gov or major regulatory databases (WEB-11, WEB-12). Preclinical proof-of-concept studies have demonstrated successful CRISPR-Cas9 correction of MPL mutations in cell s 5. ABE clinical validation: ABE8e (Richter et al. 2020, Nat Biotechnol) achieves ~1.7x higher editing efficiency than ABE7.10. VERVE-101 demonstrated first-in-human LNP-ABE liver editing with 55-66% PCSK9 reduction (Raal et al. 2025, NEJM). Beam Therapeutics is advancing multiple ABE programs.

1. No published data specifically correcting MPL c.304C>T (p.Arg102Cys) with Base Editing (ABE8e); strategy is based on general principles and must be validated preclinically.
2. PAM availability and bystander base analysis for the specific genomic context have not been performed. If no canonical NGG PAM positions the target within the editing window, PAM-flexible variants (SpRY) may be needed.
3. Long-term durability, off-target genome-wide effects, and immunogenicity in the target patient population require thorough preclinical and clinical evaluation.